The Mexican dataset of a repetitive transcranial magnetic stimulation clinical trial on cocaine use disorder patients: SUDMEX TMS

Cocaine use disorder (CUD) is a global health problem with severe consequences, leading to behavioral, cognitive, and neurobiological disturbances. While consensus on treatments is still ongoing, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising approach for medication-resistant disorders, including substance use disorders. In this context, here we present the SUDMEX-TMS, a Mexican dataset from an rTMS clinical trial involving CUD patients. This longitudinal dataset comprises 54 CUD patients (including 8 females) with data collected at five time points: baseline (T0), two weeks (T1), three months (T2), six months (T3) follow-up, and twelve months (T4) follow-up. The clinical rTMS treatment followed a double-blinded randomized clinical trial design (n = 24 sham/30 active) for 2 weeks, followed by an open-label phase. The dataset includes demographic, clinical, and cognitive measures, as well as magnetic resonance imaging (MRI) data collected at all time points, encompassing structural (T1-weighted), functional (resting-state fMRI), and multishell diffusion-weighted (DWI-HARDI) sequences. This dataset offers the opportunity to investigate the impact of rTMS on CUD participants, considering clinical, cognitive, and multimodal MRI metrics in a longitudinal framework.


Inclusion
• Minimum age of 18 years and maximum of 50 years old.
• Cocaine use for at least 1 year, with current average use of at least 3 times a week, with periods of continuous abstinence of less than one month during the last year.
• Reading level of at least 6th grade of primary school.
• Ability to give valid informed consent.

Exclusion
• First-degree personal or family history of any clinically defined neurological disorder.
• Splinters of metal or metal projectiles to the head or body.
• Current use of any investigational drug or of any medicine with anti-or pro-convulsive action such as tricyclic antidepressants or neuroleptics, unless prescribed for craving symptoms.
• History of any heart condition currently under medical care (i.e., myocardial infarction, angina pectoris, congestive heart failure, etc.) • Women with reproductive potential not using an acceptable form of contraception, as well as pregnant or lactating women.
• Any history of seizures.
• Current dependence (by DSM-5 criteria) on substances other than cocaine and / or nicotine (cocaine use disorder).
• History of HIV infection or HIV antibody test positive (due to potential neuroinfection).

Elimination
• Expressed desire to stop participating.
• Those who for any reason stopped attending rTMS sessions, for 2 or more days for those in the acute phase, or 2 weeks for those in the maintenance phase.
• Those who presented abnormal radiological findings warranting clinical attention outside the study to ensure the health of the participant.
• The appearance of psychotic symptoms related to addictive disorder.
• Presence of adverse effects related to the application of rTMS such as seizures and abnormal elevation of mood.rTMS = repeated transcranial magnetic stimulation.months.However, the maintenance phase was subsequently changed to 3 months for new enrollments (see study attrition).

Clinical Assessments details
The following instruments were used in the overall clinical trial: 1. MINI-PLUS: Is a structured diagnostic interview, of short duration in which the main psychiatric disorders of Axis I of DSM-V and ICD-10 are explored for detection and / or diagnostic orientation, It is divided into modules, identified by letters, each corresponding to a diagnostic category.At the beginning of each module (except in the psychotic disorders module), the interview has one or more "filter" questions corresponding to the main diagnostic criteria for the disorder.At the end of each module, one or more diagnostic boxes are presented that allow the interviewer to indicate whether or not the diagnostic criteria for the disorder were met.This instrument will be used for the initial evaluation of the patient and verification of the inclusion and exclusion criteria 2 .

SCID-II:
Evaluate personality disorders in a categorical way according to DSM-IV criteria.Each of the criteria is valued from the following score: 1: absent, 2: Present or true, it consists of 119 questions with a dichotomous answer that reduces the test administration time, The test was applied only in the baseline measurement (T0), since it is a constant clinical feature 3 .

SCL90 R:
The SCL-90-R is a self-applied symptom questionnaire consisting of 90 items.Each item is answered on a 5-point Likert-type scale, from "0" (absence of the symptom) to "4" (total presence of the same).By correcting the test we obtain 9 The test was applied in each clinical measurement (T0 to T4) to assess changes in symptoms in each phase 4 .

Addiction Severity Index (ASI):
The ASI is a semi-structured interview designed to address seven potential problem areas in substance-abusing patients: medical status, employment and support, drug use, alcohol use, legal status, family/social status, and psychiatric status.In 1 hour, a skilled interviewer can gather information on recent (past 30 days) and lifetime problems in all of the problem areas.The ASI provides an overview of problems related to substance, rather than focusing on any single area.The test was applied in each clinical measurement (T0 to T4) to assess changes in symptoms in each phase 5 .with some items scored inversely.For its interpretation, the total of the items is added.The test was applied at each clinical measurement (T0 to T4) to assess changes in craving in each phase 11 .

BIS11: The 11th version of the
12. Cocaine Craving visual analogue scale (VAS): This is an instrument for the subjective evaluation of the subject's craving at the present moment.The visual scale consists of a continuous 10 cm line (including 2 decimals), in which the left endpoint refers to "no craving" and the right endpoint "the most intense craving" and the subject must mark with a cross the intensity of their craving at that moment between one of the two extremes.This scale was applied in each clinical measurement (T0 to T4) to assess changes in craving in each phase 12 .
13. Alcohol breath test: An alcohol monitoring test was performed to identify the possible presence of substances in the subject before performing the MRI study.This was done in the initial evaluation (T0) and in each subsequent measurement (T1 to T4), with a breath alcohol analyzer, Lifeloc model FC10 (Wheat Ridge, CO, USA), which has a detection accuracy of ± .005BAC. 15.Reincidence/Relapse follow-up: A record of the cocaine abuse patterns of patients was carried out, to identify if they presented reincidence or relapses.This was applied in each of the subsequent measurements (T1 to T4). "Reincidence" was defined as the presence of at least one episode of consumption but without returning to previous consumption, and "relapse" was defined when consumption returned to the previous pattern.what extent there is a degree of deterioration in the interviewed person through a visual analog scale, which goes from 0 (absence of deterioration) to 5 (great deterioration).It is a descriptive scale that provides a total score and scores in each of the 4 dimensions.There are no cut points; the higher the score, the greater the disability.It was obtained in the baseline evaluation (T0) and in each of the subsequent ones (T1 to T4) 13 .

Edinburgh Handedness:
The Edinburgh Manual Laterality Inventory aims to assess manual dominance.This instrument evaluates the degree to which the subject uses the left or right hand for 4 predetermined actions and provides a numerical result, which is used to form three categories: predominant use of the left hand, similar use of both hands, and predominant use of the right hand.This instrument was applied in the baseline assessment (T0) only 14 .

Clinical outcome measures
• Primary Outcome Measures:  • Tertiary outcome measure: 1. Changes in resting state functional connectivity using magnetic resonance imaging

Transcranial magnetic stimulation
We performed a double-blind randomized controlled trial (RCT) with parallel groups (Sham/Real) with a final allocation ratio of 1:1.25 for 2 weeks of acute treatment named the acute phase, following with an open-label trial at timepoints 3, 6 and up to 12 months of chronic treatment maintenance, named the maintenance phase.The allocation was 1:1, however it would have been simple for TMS technicians to guess the group allocation for the last patients as they knew the final sample size and group membership of previous patients.
Therefore, we decided to include a bigger sample for the randomization to avoid guessing of the group.For the acute phase, we used a MagPro R30+Option magnetic stimulator and an eight-shaped B65-A/P coil (Magventure, Denmark), and for the maintenance phase, we used a MagPro R30 stimulator and an eight-shaped MCF-B70 (Magventure, Denmark).The reason for using 2 different TMS models was practical, to be able to stimulate more patients.
However, there are no differences in the induced field between models, only the cooling system and the sham possibility from the MagPro R30+Option.We used a 5-Hz excitatory frequency as is standard in our clinical setting due to the low presence of secondary effects and similar clinical improvement to 10-Hz in major depression, Alzheimer's disease, among others [15][16][17][18][19] .Safety outcomes are reported in Table S3.The motor threshold was determined in each patient as described by Rossini et al. 20 , localizing M1 from vertex 5 cm along and 2 cm anteriorly the interaural line.The coil was placed at 45°with respect to the interhemispheric fissure (anterior-medial induced current) and single pulses were applied separated by 5 seconds.The intensity that caused at least 5 responses of the abductor pollicis brevis (APB) muscle from 10 pulses was considered the MT 21 .MT was determined before the first session and on the 6th day of treatment.For the maintenance phase, MT was determined in each session (once per week).We localized left DLPFC using the 5 cm method in the first 16 participants and the Beam F3 method (Beam, Borckardt, Reeves, & George, 2009) in the rest of the subjects to optimize DLPFC localization (only n = 11 were available at the time for this analysis).Sham electrodes were placed to simulate muscle contraction in the Sham group.The acute phase comprised 10 weekdays of 5,000 pulses per day (two sessions of 50 trains at 5 Hz, 50 pulses/train, 10 s inter-train interval and 15 min inter-session interval).The maintenance phase comprised 3 and 6 months of 5,000 pulses per day, 2 sessions per week.The motor threshold was maintained at 100% in all patients.Because a Brain Navigator was not available, we used a vitamin E capsule fiducial during MRI acquisition to identify the actual stimulation target where rTMS was delivered in n = 27.EMS oversaw all rTMS sessions and determined the capsule's location before the first MRI session using either the 5.5 cm anatomic criterion or the Beam F3 method (Table S4 & Fig. S2).We changed to the superior Beam F3 method after the first 16 participants to improve lDLPFC localization 22 .EMS marked lDLPFC on the scalp with a marker, then maintained the capsule's position using removable tape and a swimmer's cap.
scales and 3 indexes of psychological distress.The symptomatic scales are as follows: Somatization, Obsession-compulsion, Interpersonal sensitivity, Depression, Anxiety, Hostility, Phobic anxiety, Paranoid ideation and Psychoticism.The discomfort indices are: a) the global severity index (GSI), b) the positive symptomatic discomfort index (PSDI) and c) the total of positive symptoms (PST).

6 . 7 . 8 . 9 . 10 .
Barratt Impulsivity Scale is one of the most widely used instruments for assessing impulsivity.Its application is self-administered and it consists of 30 questions, grouped into three subscales: Cognitive impulsivity, Motor impulsiveness, Unplanned impulsiveness.Each of the questions has 4 possible answers (rarely or never, occasionally, often and always or almost always.The total score is the sum of all the items and the total of the subscales are the sum of the items corresponding to each of them6 .Hamilton Depression Rating Scale (HDRS): The Hamilton Rating Scale for Depression was used to provide a measure of the severity of depression.The version we used is the one of 17 items, recommended by the United States National Institute of Mental Health.Its content focuses on the basic aspects and behavior of depression, with vegetative, cognitive and anxiety symptoms having the greatest weight in the total calculation of the scale.The cutoff points to define severity are: no depression (0-7); mild depression(8-16); moderate depression(17-23); and severe depression (≥24).This scale was applied in the basal measurement (T0) and all subsequent measurements.The test was applied in each clinical measurement (T0 to T4) to assess changes in symptoms in each phase7 .Hamilton Anxiety Rating Scale (HARS): This scale assesses the severity of anxiety globally and is useful for monitoring response to treatment.It is made up of 14 items, with 13 references to anxious signs and symptoms and the last one that evaluates the patient's behavior during the interview.The interviewer scores from 0 to 4 points each item, assessing both its intensity and frequency.The total score is the sum of those of each of the articles.The range is from 0 to 56 points.The optimal HAM-A score ranges were: no/minimal anxiety ≤ 7; mild anxiety = 8-14; moderate = 15-23; severe ≥ 24.The test was applied in each clinical measurement (T0 to T4) to assess changes in symptoms in each phase8 .Pittsburgh Sleep Quality Index (PSQI): This instrument has been created to measure the quality of sleep in patients with psychiatric disorders.It is made up of 24 items, although only 19 are taken into account for its correction.In addition, it is divided into 7 dimensions: Subjective sleep quality, Sleep latency.Duration of sleep, Usual sleep efficiency, Sleep disturbances, Use of medication, Daytime dysfunction.It is answered with a Likert-type scale that goes from 0 to 4. For its correction, a sleep profile is obtained in each of the dimensions ranging from 0 to 3 and a total score that can range from 0 to 21.The test was applied in each clinical measurement (T0 to T4) to assess changes in symptoms in each phase9 .Treatment-As-Usual follow-up: Consists of a record of the treatment that each subject had indicated at the beginning of the study, which was prescribed by the treating physician in the addiction clinic of the National Institute of Psychiatry, according to the protocols that they normally follow.The record indicated whether the subject received psychotherapy and/or pharmacological treatment, together with the type of psychotherapy and the name of the drug received, as well as changes to these treatments in each of the following measurements.This record was made in a format created for the present study which was applied both in the baseline assessment and in each of the subsequent assessments.Timeline Followback Method Assessment modified (mTLFB): This is a record of the pattern of cocaine/crack use of each subject, made on a calendar-based format, where the consumption of the last two years up to the present was evaluated, indicating the number of days of use per month and the amount in grams consumed each full month (30 days).This format was applied in the baseline measurement (T0) where previous consumption was recorded and in each subsequent measurement to assess the longitudinal pattern of substance use every month before and during the trial10 .11. Cocaine Craving Questionnaire (CCQ): This instrument evaluates the intensity of cocaine craving.The version used in this study has a format that evaluates craving at the present time, and a format that evaluates the general state of craving during the last week.Each form consists of 45 items, each item is made up of a 7-point Likert scale in which the subject must indicate their degree of agreement or disagreement,

14 .
Urine drug test: Performed to identify the possible presence of substances of abuse in subjects prior to performing the MRI study.This test was performed with a Kabla (Monterrey, NL, Mexico) reagent strip device, model Instant view-Drug screen, using the lateral flow chromatographic immunoassay technique.The substances detected and their cut-off points are as follows: Amphetamines (1000 ng/mL), Benzodiazepines (300 ng/mL), Cocaine (300 ng/mL), Methamphetamine (1000 ng/mL), Morphine/Opiates (2000 ng/mL), Marijuana/Hashish (50 ng/mL).This test was applied in the baseline measurement and each of the subsequent ones.Results in Tables S6 & S7.

16 .
WHODAS: Instrument that assesses the psychological and social functioning of people affected by a mental disorder.It provides information on four areas: Personal Care, Occupation, Family/Housing and Social Functioning.The clinician scores to

7 . 8 .
Lapse rate [ Time Frame: Baseline, 2 weeks, 3 months ]: Lapse is defined as at least one consumption event not in the same pattern as the baseline consumption.The report of self-consumption of cocaine and urine drug tests, with special attention to the presence of traces of cocaine.Relapse rate [ Time Frame: Baseline, 2 weeks, 3 months ]: Relapse is defined as consumption events in the same pattern as the baseline consumption.The report of self-consumption of cocaine and urine drug tests, with special attention to the presence of traces of cocaine.

table 2 .
Standard treatments received by each participant during rTMS therapy.

34 Treatment yes no yes 2 topiramate NA NA 35 Treatment yes no yes 3 topiramate fluoxetine atomoxetine 37 Treatment yes no yes 1 topiramate NA NA 38 Treatment yes no yes 3 topiramate mirtazapine NA 39 Treatment yes no yes 2 topiramate trazodone NA 41 Treatment yes no yes 3 topiramate citalopram gabapentin 43 Treatment yes no yes 2 fluoxetine topiramate NA 48 Treatment yes yes yes 3 fluoxetine topiramate hydroxyzine 49 Treatment yes no yes 2 fluoxetine topiramate NA 51 Treatment yes no yes 3 topiramate fluoxetine NA 53 Treatment yes yes yes 2 valproic acid quetiapine NA 54 Treatment yes yes yes 3 fluoxetine topiramate atomoxetine The psychosocial treatment consisted of group therapy with a motivational approach focused on addiction, received at the addiction clinic of the National Institute of Psychiatry. Supplementary figure 13. CONSORT flow diagram.
to continue, received 2-weeks (10 days) acute treatment before continuing to the maintenance phase.The maintenance phase was initially designed to include 2 weekly rTMS sessions and clinical assessments and MRI scans at 3 months, 6 months and 12

table 15 .
Subsequently, EMS checked the capsule location before scanning.That same marked location on the scalp based on the coordinates at which the fucidal (capsule) was placed was used for rTMS sessions.Safety outcomes for the acute phase.

table 16 .
Type of lDLPFC localization per patient.